tretinoin and Lung-Diseases

Retinoic acid (RA) is a key molecular player in embryogenesis and adult tissue homeostasis. In embryo development, RA plays a crucial role in the formation of different organ systems, namely, the respiratory system. During lung development, there is a spatiotemporal regulation of RA levels that assures the formation of a fully functional organ. RA signaling influences lung specification, branching morphogenesis, and alveolarization by regulating the expression of particular target genes. Moreover, cooperation with other developmental pathways is essential to shape lung organogenesis. This review focuses on the events regulated by retinoic acid during lung developmental phases and pulmonary vascular development; also, it aims to provide a snapshot of RA interplay with other well-known regulators of lung development.

Topics: Animals; Gene Expression Regulation, Developmental; Humans; Lung; Lung Diseases; Pulmonary Artery; Pulmonary Veins; Signal Transduction; Tretinoin

Retinoic acid (RA), the bioactive metabolite of vitamin A (VA), has long been recognized as a critical regulator of the development of the respiratory system. During embryogenesis, RA signaling is involved in the development of the trachea, airways, lung, and diaphragm. During postnatal life, RA continues to impact respiratory health. Disruption of RA activity during embryonic development produces dramatic phenotypes in animal models and human diseases, including tracheoesophageal fistula, tracheomalacia, congenital diaphragmatic hernia (CDH), and lung agenesis or hypoplasia. Several experimental methods have been used to target RA pathways during the formation of the embryonic lung. These have been performed in different animal models using gain- and loss-of-function strategies and dietary, pharmacologic, and genetic approaches that deplete retinoid stores or disrupt retinoid signaling. Experiments utilizing these methods have led to a deeper understanding of RA's role as an important signaling molecule that influences all stages of lung development. Current research is uncovering RA cross talk interactions with other embryonic signaling factors, such as fibroblast growth factors, WNT, and transforming growth factor-beta.

Topics: Animals; Humans; Intercellular Signaling Peptides and Proteins; Lung Diseases; Respiratory System; Signal Transduction; Tretinoin

Neurofibromatosis type 1 (NF-1), also known as von Recklinghausen's disease, is an autosomal dominant dysplasia of the ectoderm and mesoderm with a variable clinical expression, but near-complete penetrance before the age of 5 years. The estimated incidence is 1 in 3000 births. NF-1 is characterized by collections of neurofibromas, café-au-lait spots, axillary and inguinal freckling, and pigmented hamartomas in the iris (Lisch nodules). Pulmonary manifestations of NF-1, which usually include bilateral basal reticulations and apical bullae and cysts, are reported in 10-20% of adult patients. Clinically, neurofibromatosis-associated diffuse lung disease (NF-DLD) usually presents with nonspecific respiratory symptoms, including dyspnea on exertion, shortness of breath, and chronic cough or chest pain, at the time of diagnosis. Computed tomography (CT) is highly accurate for the identification and characterization of NF-DLD; it is the most reliable method for the diagnosis of this lung involvement. Various CT findings of NF-DLD, including cysts, bullae, ground-glass opacities, bibasilar reticular opacities, and emphysema, have been described in patients with NF-1. The typical CT pattern, however, is characterized by upper-lobe cystic and bullous disease, and basilar interstitial lung disease. Currently, the goal of NF-DLD treatment is the earliest possible diagnosis, focusing on symptom relief and interventions that positively alter the course of the disease, such as smoking cessation. The aim of this review is to describe the main clinical, pathological, and imaging aspects of NF-1, with a focus on pulmonary involvement.

Topics: Acrylonitrile; Aged; Aniline Compounds; Antineoplastic Agents; Benzimidazoles; Blister; Child; Female; Genetic Counseling; Humans; Hypertension, Pulmonary; Lung Diseases; Lung Diseases, Interstitial; Male; Middle Aged; Neurofibromatosis 1; Pulmonary Emphysema; Tomography, X-Ray Computed; Tretinoin; Young Adult

Epithelial-mesenchymal interactions and extracellular matrix remodeling are key processes of embryonic lung development. Lung smooth muscle cells, which are derived from the mesenchyme, form a sheath around bronchi and blood vessels. During lung organogenesis, smooth muscle differentiation coincides with epithelial branching morphogenesis and closely follows developing airways spatially and temporally. The precise function of parabronchial smooth muscle (PBSM) cells in healthy adult lung remains unclear. However, PBSM may regulate epithelial branching morphogenesis during lung development by the induction of mechanical stress or through regulation of paracrine signaling pathways. Alveolar myofibroblasts are interstitial contractile cells that share features and may share an origin with smooth muscle cells. Alveolar myofibroblasts are essential for secondary septation, a process critical for the development of the gas-exchange region of the lung. Dysregulation of PBSM or alveolar myofibroblast development is thought to underlie the pathogenesis of many lung diseases, including bronchopulmonary dysplasia, asthma, and interstitial fibrosis. We review the current understanding of the regulation of PBSM and alveolar myofibroblast development, and discuss the role of PBSM in lung development. We specifically focus on the role of these cells in the context of fibroblast growth factor-10, sonic hedgehog, bone morphogenetic protein-4, retinoic acid, and Wnt signaling pathways in the regulation of lung branching morphogenesis.

Topics: Animals; Bone Morphogenetic Protein 4; Bone Morphogenetic Proteins; Bronchi; Extracellular Matrix; Fibroblast Growth Factor 10; Fibroblasts; Hedgehog Proteins; Humans; Lung Diseases; Myocytes, Smooth Muscle; Organogenesis; Pulmonary Alveoli; Trans-Activators; Tretinoin; Wnt1 Protein

The lung has significant susceptibility to injury from a variety of chemotherapeutic agents. The clinician must be familiar with classic chemotherapeutic agents with well-described pulmonary toxicities and must also be vigilant about a host of new agents that may exert adverse effects on lung function. The diagnosis of chemotherapy-associated lung disease remains an exclusionary process, particularly with respect to considering usual and atypical infections, as well as recurrence of the underlying neoplastic process in these immune compromised patients. In many instances, chemotherapy-associated lung disease may respond to withdrawal of the offending agent and to the judicious application of corticosteroid therapy.

Topics: Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Bleomycin; Busulfan; Camptothecin; Cyclophosphamide; Humans; Iatrogenic Disease; Interferons; Irinotecan; Lung Diseases; Methotrexate; Mitomycin; Nitrosamines; Respiratory Function Tests; Tretinoin

Retinoic acid is the bioactive metabolite of vitamin A and considerable evidence implicates retinoic acid as important signaling molecule during normal lung development and retinoid signaling elements, such as receptors and binding proteins have been described in the developing lung. Alveolization, or the formation of alveoli during lung development, is essentially completed in the neonatal period, and little neo-alveolization occurs in the adult lung. Recently, several studies have shown that retinoic acid is effective in promoting alveolization in neonatal rats, in adult rats with elastase-induced emphysema. However, the exact mechanism governing this regeneration is still unknown. Recent advanced technologies will clarify the role of retinoic acid in alveolization and even how alveolization occurs, leading to regeneration therapy for the devastating lung diseases, such as emphysema and fibrotic disorders.

Topics: Animals; Humans; Lung Diseases; Pulmonary Alveoli; Pulmonary Emphysema; Pulmonary Fibrosis; Regeneration; Signal Transduction; Tretinoin

All-trans retinoic acid (ATRA) has recently been recognized as the first line therapeutic agent in the treatment of patients with acute promyelocytic leukemia (APL). The extraordinary high remission rate achieved by ATRA in comparison with other chemotherapeutic agents suggested that ATRA differentiation induction therapy seemed superior to conventional chemotherapy for APL patients. However, after the great excitement aroused after the initial successes, we have to take stock and examine in detail several problems which have emerged preventing us from improving the clinical outcome in APL. Maintenance in order to prolong remission and prevention of or retreatment for the relapse are the major subjects of concern at present. Efforts should be made either to keep ATRA effective for APL patients or to resensitize the relapsing patients for repeated ATRA therapy. The administration of ATRA should be carefully adapted in accordance with the individual patient's condition. From both conceptual and practical points of view, ATRA differentiation therapy should be combined with chemotherapy, bone marrow transplantation and biomodifier treatment. Thus, a more comprehensive strategy must be planned and developed in the near future. Using molecular biological techniques, the diagnosis of APL can be more precisely made and the course of the disease more closely monitored. The central dogma, still to be revealed, is the relationship between APL pathogenesis, the chromosome translocation present with the relevant molecular alterations and the response to ATRA treatment. Current studies in all these above fields have provided us with a deeper understanding of the pathogenesis of APL and the physiological function and curative action of ATRA.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Antineoplastic Combined Chemotherapy Protocols; Drug Evaluation; Edema; Fever; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Lung Diseases; Remission Induction; Syndrome; Treatment Outcome; Tretinoin

Epidemiological studies suggested that vitamin A may be protective against lung cancer, however, recent chemoprevention trials with beta-carotene, a precursor of vitamin A, demonstrated enhancement of lung carcinogenesis among smokers. Whether vitamin A is beneficial or harmful in chemoprevention of lung cancer in smokers has not been resolved. This study was designed to determine the effect of retinol alone in current and former smokers using bronchial dysplasia, nuclear morphometry and retinoic acid receptor-beta (RAR-beta) mRNA expression as surrogate end-point biomarkers (SEBs). Eighty-one current or former smokers with a smoking history of >/=30 pack-years were randomized to receive either placebo or retinol (50,000 IU per day) for six months. Fluorescence bronchoscopy was performed prior to treatment to localize areas suggestive of dysplasia. At least 4 bronchial biopsies were taken per subject including at least two biopsies from apparently normal areas. The same areas were precisely re-biopsied after 6 months. Any new areas suggestive of dysplasia were also biopsied. Changes in the SEBs were assessed before and after treatment. At baseline, the frequency of biopsies negative for RAR-beta expression was: normal (23%), hyperplasia (28%), metaplasia (41%), mild dysplasia (41%), and moderate/severe dysplasia (44%). There was no significant difference in the regression rate between the retinol and placebo groups using histopathology and nuclear morphometry as SEBs. The likelihood of regression was found to be lower in those who continued to smoke during the study (OR=1.86 for those smoking >10 cigarettes per day, p=0.084 to OR=0.95, p=0.26 for those smoking 20+ per day compared to ex-smokers). Retinol was not effective in the up-regulation of RAR-beta in lesions with bronchial dysplasia. We postulate that the lack of effect of retinol on RAR-beta expression among individuals who continued to smoke while taking retinol may be due to suppressive effect of tobacco smoke constituents on RAR-beta expression and/or altered cellular metabolism of retinol to retinoic acid and its isomers.

Topics: Aged; Anticarcinogenic Agents; Biomarkers; Biomarkers, Tumor; Biopsy; Bronchoscopy; Cell Nucleus; Chemoprevention; Female; Humans; Lung Diseases; Lung Neoplasms; Male; Metaplasia; Middle Aged; Odds Ratio; Placebos; Receptors, Retinoic Acid; RNA, Messenger; Smoking; Time Factors; Tretinoin; Vitamin A

All-trans retinoic acid (ATRA) induces complete remission (CR) in most cases of acute promyelocytic leukemia (APL) but its use is associated with potentially fatal pulmonary toxicity in approximately 25% of APL patients in the setting of a rapidly rising peripheral blood white cell count (WBC). The efficacy of oral corticosteroid for prophylaxis against pulmonary toxicity has been investigated in a prospective multi-center study. ATRA was administered at 45 mg/m2/day as single agent therapy throughout induction treatment in 19 patients with an initial WBC < 10 x 10(9)/l, and prednisolone 75 mg/day was added in those 12 patients in whom the WBC rose above 10 x 10(9)/l. Combination chemotherapy plus prednisolone was added to ATRA in six other patients on the basis of criteria specified in the protocol. All 19 patients who received ATRA without chemotherapy achieved CR without signs of pulmonary toxicity despite a rise in WBC to peak values as high as 112 x 10(9)/l. Pulmonary toxicity developed in two patients commenced on ATRA in association with an unusually rapid increment in WBC of 7.5 x 10(9)/l and 32.5 x 10(9)/l in the first 2 days; both were subsequently treated with chemotherapy. The low incidence of pulmonary toxicity in this study compared with that in previous trials suggests that prednisolone prophylaxis increases safety of ATRA therapy in APL irrespective of the peak WBC.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Drug Interactions; Humans; Leukemia, Promyelocytic, Acute; Leukocyte Count; Lung Diseases; Middle Aged; Prednisolone; Prospective Studies; Remission Induction; Tretinoin

Although arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) are well-tolerated and effective treatments for Acute Promyelocytic Leukemia (APL), Differentiation Syndrome (DS) is a lethal side effect in some patients. The pathogenesis of DS is complex and not well understood; however, it is considered as an inflammatory response due to cytokines release of differentiated cells. Moreover, adhesion molecules that are widely expressed on the surface of differentiated cells and gene expression changes of transglutaminase2 (TGM2) are mechanisms involved in the development of DS. The purpose of this study was to assess the association of single nucleotide polymorphisms (SNP) of Intercellular Adhesion Molecule-1 (ICAM-1), chemokine (C-C motif) ligand 2 (CCL2) and TGM2 as inflammatory factors with differentiation syndrome susceptibility.. DNA was extracted from 133 APL patients and 100 normal controls. Assessment according to the PETHEMA criteria revealed that 13.5% of these patients experienced differentiation syndrome. Tetra-ARMS PCR and PCR-RFLP were done to amplify DNA fragments in APL patients with and without DS. Then DNA sequencing was done to validate the results. SNPStats, SPSS and Finch TV were used to analyze the results.. A significant correlation was found between rs4811528 in the TGM2 gene and differentiation syndrome susceptibility (P = 0.002, 95% CI = 1.74-18.81, OR = 5.72) while rs5498 in ICAM-1, rs1024611 in CCL2, and rs7270785 in TGM2 genes showed no correlation with differentiation syndrome. The G allele of rs7270785 and rs4811528 showed a haplotypic association with differentiation syndrome (P = 0.03, 95% CI = 1.13-13.86, OR = 3.96).. AA genotype of the TGM2 SNP (rs4811528) may be a risk factor for development of DS in patients with APL following the use of ATRA/ATO.

Topics: Acute Kidney Injury; Adult; Antineoplastic Agents; Biomarkers, Tumor; Case-Control Studies; Cell Differentiation; Chemokine CCL2; Female; Follow-Up Studies; GTP-Binding Proteins; Humans; Intercellular Adhesion Molecule-1; Leukemia, Promyelocytic, Acute; Lung Diseases; Male; Polymorphism, Genetic; Prognosis; Protein Glutamine gamma Glutamyltransferase 2; Survival Rate; Syndrome; Systemic Inflammatory Response Syndrome; Transglutaminases; Tretinoin

This study shows a causal association between ALDH1A2 variants and a novel, severe multiple congenital anomaly syndrome in humans that is neonatally lethal due to associated pulmonary hypoplasia and respiratory failure. In two families, exome sequencing identified compound heterozygous missense variants in ALDH1A2. ALDH1A2 is involved in the conversion of retinol (vitamin A) into retinoic acid (RA), which is an essential regulator of diaphragm and cardiovascular formation during embryogenesis. Reduced RA causes cardiovascular, diaphragmatic, and associated pulmonary defects in several animal models, matching the phenotype observed in our patients. In silico protein modeling showed probable impairment of ALDH1A2 for three of the four substitutions. In vitro studies show a reduction of RA. Few pathogenic variants in genes encoding components of the retinoic signaling pathway have been described to date, likely due to embryonic lethality. Thus, this study contributes significantly to knowledge of the role of this pathway in human diaphragm and cardiovascular development and disease. Some clinical features in our patients are also observed in Fryns syndrome (MIM# 229850), syndromic microphthalmia 9 (MIM# 601186), and DiGeorge syndrome (MIM# 188400). Patients with similar clinical features who are genetically undiagnosed should be tested for recessive ALDH1A2-deficient malformation syndrome.

Topics: Abnormalities, Multiple; Aldehyde Dehydrogenase 1 Family; Animals; Cardiovascular Diseases; Diaphragm; Humans; Lung Diseases; Retinal Dehydrogenase; Syndrome; Tretinoin

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Diagnosis, Differential; Dyspnea; Female; Fever; Humans; Hypotension; Leukemia, Promyelocytic, Acute; Leukocytosis; Lung Diseases; Oxides; Risk Factors; Severity of Illness Index; Syndrome; Treatment Outcome; Tretinoin

Reports about patients with acute promyelocytic leukemia from the Middle East are few; in this study we are reporting our single center experience of treating 29 patients over 6years. Acute promyelocytic leukemia treatment response is markedly improved after the introduction of ATRA. Treatment related complication is still an important issue particularly Differentiation Syndrome. Prediction to its occurrence has been tried by other groups. We aimed to study all the possible predictive factors of acute promyelocytic leukemia. Our chemotherapy induction protocol is AIDA protocol which includes ATRA 45mg/m(2)/d in divided doses every12h, and Idarubicin 12mg/m(2)/d IV on days 3, 5, 7, and 9. Differentiation Syndrome occurred in 48.3% of patients and was mainly presented by pulmonary symptoms in 55.2%, 6 cases died during induction. None of the predictive factors studied showed a statistically significant difference between patients who developed Differentiation Syndrome and those who did not. Differentiation Syndrome did not affect overall survival. Cox regression showed an inverse yet a non significant association between PETHEMA and overall survival probability (P=0.168). In conclusion, Differentiation Syndrome has no clear predictive factor to date. The best approach is to hold ATRA and give dexamethasone which is quite effective as reported in the literature. PETHEMA risk model has a moderately significant prognostic value.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Female; Fever; Hemorrhage; Humans; Kaplan-Meier Estimate; Leukemia, Promyelocytic, Acute; Lung Diseases; Male; Middle Aged; Proportional Hazards Models; Risk Factors; Syndrome; Tretinoin; Young Adult

All-trans retinoic acid (ATRA), a vitamin A derivative, is prescribed for induction of chemotherapy in patients with acute promyelocytic leukemia. Like other chemotherapy agents, ATRA has an adverse effect known as retinoic acid syndrome. The case of a 22 year old woman with acute promyelocytic leukemia, who received ATRA and subsequently developed retinoic acid syndrome, is presented. The patient's symptoms resolved after administration of dexamethasone, allowing the completion of chemotherapy without further complications.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Female; Glucocorticoids; Humans; Hypotension; Intraoperative Complications; Leukemia, Promyelocytic, Acute; Lung Diseases; Postoperative Complications; Syndrome; Tooth Extraction; Tretinoin; Young Adult

Prenatal treatment with retinoic acid (RA) has been reported to stimulate alveologenesis in hypoplastic lungs (HL) in the nitrofen model of congenital diaphragmatic hernia (CDH). Parathyroid hormone-related protein (PTHrP) promotes alveolar maturation by stimulating surfactant production, regulated by PTHrP receptor (PTHrP-R). PTHrP knockout and PTHrP-R null mice both exhibit pulmonary hypoplasia. We have recently reported that nitrofen inhibits PTHrP signaling in the nitrofen-induced HL. Because both PTHrP and PTHrP-R genes have RA-inducible element, we hypothesized that prenatal administration of RA upregulates pulmonary gene expression of PTHrP and PTHrP-R in the nitrofen-induced HL.. Pregnant rats were exposed to either olive oil or nitrofen on day 9 of gestation (D9). RA was given on days D18, D19 and D20. Fetal lungs were obtained on D21 and divided into four groups: control, control + RA, nitrofen, nitrofen + RA. RT-PCR and Immunohistochemistry were performed to investigate the pulmonary PTHrP and PTHrP-R gene and protein expression in each group, respectively.. The pulmonary gene expression levels of PTHrP and PTHrP-R were significantly increased in nitrofen + RA group compared to nitrofen group (p < 0.05). Immunoreactivity of PTHrP and PTHrP-R was also remarkably increased in nitrofen + RA group compared to nitrofen group.. Upregulation of PTHrP and PTHrP-R genes after prenatal treatment with RA in the nitrofen-induced HL suggests that RA may have a therapeutic potential in reverting lung hypoplasia in CDH, by stimulating surfactant production and alveolar maturation.

Topics: Analysis of Variance; Animals; Disease Models, Animal; Female; Lung; Lung Diseases; Olive Oil; Parathyroid Hormone-Related Protein; Phenyl Ethers; Plant Oils; Pregnancy; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Tretinoin; Up-Regulation

Pulmonary hypoplasia (PH), the leading cause of mortality in congenital diaphragmatic hernia (CDH), is associated with arrested alveolarization. Late gestation lung protein 1 (LGL1) plays a crucial role in the regulation of alveolarization. Inhibition of LGL1 impairs alveolar maturation in fetal rat lungs. LGL1 heterozygotus knockout mice display delayed lung maturation. It is well known that prenatal administration of retinoic acid (RA) stimulates alveologenesis in nitrofen-induced PH. In vitro studies have reported that RA is a key modulator of LGL1 during alveologenesis. We hypothesized, that pulmonary gene expression of LGL1 is downregulated in the late stage of lung development, and that prenatal administration of RA upregulates pulmonary LGL1 expression in the nitrofen CDH model.. Pregnant rats were exposed to nitrofen on day 9 (D9) of gestation. RA was given intraperitoneally on D18, D19 and D20. Fetal lungs were dissected on D21 and divided into control, control + RA, CDH and CDH + RA group. Expression levels of LGL1 were determined using RT-PCR and immunohistochemistry.. On D21, LGL1 relative mRNA expression levels were significantly downregulated in CDH group compared to controls. After RA treatment, gene expression levels of LGL1 were significantly upregulated in CDH + RA and control + RA compared to CDH group. Immunohistochemical studies confirmed these results.. Downregulation of pulmonary LGL1 gene expression in the late stage of lung development may interfere with normal alveologenesis. Upregulation of LGL1 pulmonary gene expression after RA treatment may promote lung growth by stimulating alveologenesis in the nitrofen CDH model.

Topics: Animals; Female; Gene Expression Regulation, Developmental; Gestational Age; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Immunohistochemistry; Lung; Lung Diseases; Phenyl Ethers; Pregnancy; Pregnancy, Animal; Proteins; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tretinoin

Pulmonary hypoplasia (PH) is the main cause of mortality in newborns with congenital diaphragmatic hernia (CDH). Prenatal administration of retinoic acid (RA) stimulates alveologenesis in the nitrofen-induced pulmonary hypoplasia. Insulin-like growth factor receptors (IGFRs) play a crucial role in alveologenesis during lung development. We recently demonstrated that IGFRs were downregulated in later stages of lung development in the nitrofen CDH model. Several studies suggest the ability of RA to regulate insulin-like growth factor signaling. We hypothesized that IGFRs pulmonary gene expression is upregulated after the administration of RA in the nitrofen-induced CDH model.. Pregnant rats were exposed to either olive oil or nitrofen on day 9 (D9) of gestation. RA was given intraperitoneally on days D18, D19, and D20. Fetal lungs were dissected on D21 and divided into control, control + RA, CDH, and CDH + RA group. IGFRs gene and protein expression were determined using RT-PCR and immunohistochemistry.. mRNA expression levels of IGFRs were significantly increased in control + RA and CDH + RA compared with CDH group. Immunoreactivity of IGFRs was markedly increased in control + RA and CDH + RA compared with CDH lungs.. Upregulation of pulmonary gene and protein expression of IGFRs after prenatal RA treatment in the nitrofen model suggests that RA may promote lung growth by stimulating IGFRs mediated alveologenesis.

Topics: Animals; Animals, Newborn; Disease Models, Animal; Down-Regulation; Female; Gene Expression Regulation, Developmental; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Immunohistochemistry; Lung; Lung Diseases; Phenyl Ethers; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Receptor, IGF Type 1; Receptor, IGF Type 2; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tretinoin; Up-Regulation

Topics: Aged; Antineoplastic Agents; Humans; Leukemia, Promyelocytic, Acute; Lung Diseases; Lymphohistiocytosis, Hemophagocytic; Male; Syndrome; Tretinoin; Weight Gain

Research has indicated that excessive vitamin A can have deleterious impacts on bone. Retinoic acid (RA), the most active metabolite of vitamin A, has been tested in clinical trials for treatment of lung cancer and emphysema. These trials are not measuring Bone Mineral Content (BMC) or Bone Mineral Density (BMD). In this study, we used an animal model to determine potential deleterious effects of all-trans RA on bone mass when used as a means to protect against or treat cigarette smoke-induced lung injuries, and also to evaluate BMC as a potential early indicator of osteoporosis risk. Twenty-four male weanling rats were fed either a control diet or a RA-supplemented diet. Half of each group was exposed to 40 cigarettes per day, 5 days per week, for 4 weeks. BMC and BMD were measured at weeks 2 and 4. RA supplementation in all groups significantly decreased (p < 0.05) only BMC at week 2 and both BMC and BMD (both p < 0.05) at week 4. The same results were observed when BMC was expressed relative to body weight. These data suggest that caution should be used when RA is used to treat smoke-related lung injuries.

Topics: Absorptiometry, Photon; Animals; Atmosphere Exposure Chambers; Biomarkers; Bone Density; Bone Resorption; Dietary Supplements; Early Diagnosis; Lung Diseases; Male; Osteoporosis; Pulmonary Emphysema; Random Allocation; Rats; Rats, Sprague-Dawley; Smoking; Time Factors; Tretinoin; Weaning; Weight Gain

Neonatal exposure to hyperoxia alters lung development in mice. We tested if retinoic acid (RA) treatment is capable to affect lung development after hyperoxic injury and to maintain structural integrity of lung. The gene of vascular endothelial growth factor A (VEGF-A) is one of the RA-responsive genes. Newborn BALB/c mice were exposed to room air, 40% or 80% hyperoxia for 7 days. One half of animals in each group received 500 mg/kg retinoic acid from day 3 to day 7 of the experiment. At the end of experiment we assessed body weight (BW), lung wet weight (LW), the wet-to-dry lung weight ratio (W/D) and the expression of mRNA for VEGF-A and G3PDH genes. On day 7 the hyperoxia-exposed sham-treated mice (group 80) weighed 20% less than the room air-exposed group, whereas the 80% hyperoxic group treated with RA weighed only 13% less than the normoxic group. W/D values in 80 and 80A groups did not differ, although they both differed from the control group and from 40 groups. There was a significant difference between 40 and 40A groups, but the control group was different from 40 group but not from 40A groups. The 80 and 80A groups had mRNA VEGF-A expression lowered to 64% and 41% of the control group. RA treatment of normoxic and mild hyperoxic groups increased mRNA VEGF-A expression by about 50%. We conclude that the retinoic acid treatment of newborn BALB/c mice exposed for 7 days to 80% hyperoxia reduced the growth retardation in the 80 % hyperoxic group, reduced the W/D ratio in the 40% but not in the 80 % hyperoxic group. Higher VEGF-A mRNA expression in the 80% hyperoxic group treated with RA was not significant compared to the 80% hyperoxic group.

Topics: Analysis of Variance; Animals; Animals, Newborn; Antioxidants; Disease Models, Animal; Gene Expression Regulation, Developmental; Glyceraldehyde-3-Phosphate Dehydrogenases; Hyperoxia; Lung Diseases; Mice; Mice, Inbred BALB C; Pulmonary Alveoli; RNA, Messenger; Severity of Illness Index; Transcription, Genetic; Tretinoin; Vascular Endothelial Growth Factor A

Retinoids are a group of molecules derived from vitamin A, which play an important role in lung development. Within the cell, retinol can either be oxidized to retinal or esterified to retinyl esters by lecithin : retinol acyltransferase (LRAT) for storage. Retinal is then oxidized to an active metabolite of vitamin A, retinoic acid (RA) by retinal dehydrogenase (RALDH). RA is the active metabolite of vitamin A. Cyp26 (a1,b1, and c1), which is a member of the cytochrome P450 family, acts by reducing the activity of RA. Cyp26 type b1 is the predominant subtype expressed in the murine lung. Several studies have suggested that nitrofen may interfere with the retinoid pathway resulting in congenital diaphragmatic hernia (CDH) and pulmonary hypoplasia. Recently, it was reported that nitrofen may act by inhibiting RALDH2. The aim of this study was to examine the pulmonary expression of Cyp26b1, LRAT, and RALDH2, the key enzymes involved in the synthesis of RA, in order to understand the mechanisms underlying pulmonary hypoplasia in the nitrofen CDH model. Pregnant rats were exposed to either olive oil or 100 mg of nitrofen on day 9 of gestation (D9). Fetal lungs were harvested at D15, D17, D19, and D21. D17, D19, and D21 lungs were divided into three groups: control, nitrofen without CDH and nitrofen with CDH, whereas D15 lungs were divided into only two groups; control and nitrofen as the diaphragm is not fully formed yet at this stage. Real- time PCR was performed to evaluate the relative level of Cyp26b1, LRAT, and RALDH2 expression in the lung. Relative levels of Cyp26b1 mRNA were significantly decreased in the lungs of nitrofen with CDH (D17;0.19 +/- 0.09, D19;0.70 +/- 0.20, D21;0.40 +/- 0.36) and nitrofen without CDH (D17;0.14 +/- 0.06, D19;0.54 +/- 0.42, D21;0.51 +/- 0.56) compared to controls (D17;0.35 +/- 0.16, D19;1.15 +/- 0.48, D21;1.28 +/- 0.78) (P < 0.05). LRAT expression was also significantly decreased in nitrofen with CDH (D17; 19.3 +/- 7.8, D19; 4.3 +/- 1.1, D21; 3.3 +/- 1.6) and nitrofen without CDH (D17; 21.2 +/- 11.1, D19; 4.5 +/- 3.6, D21; 4.1 +/- 1.6) compared to controls (D17; 153.7 +/- 29.8, D19; 26.8 +/- 16.8 D21; 10.1 +/- 3.8) (P < 0.05). There was no significant difference in the relative levels of Cyp26b1 and LRAT between nitrofen with CDH and nitrofen without CDH. There were no significant differences in RALDH2 expression among the groups at any stages. Down-regulation of Cryp26b1 and LRAT demonstrates that RA content is decreased i

Topics: Acyltransferases; Animals; Cytochrome P-450 Enzyme System; Disease Models, Animal; Down-Regulation; Female; Gene Expression Regulation, Developmental; Herbicides; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Lung; Lung Diseases; Olive Oil; Phenyl Ethers; Plant Oils; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Retinal Dehydrogenase; Retinoic Acid 4-Hydroxylase; Reverse Transcriptase Polymerase Chain Reaction; Tretinoin

All-trans retinoic acid (ATRA) stimulates platelet-derived growth factor (PDGF)-A expression and enhances alveolarization in rat lungs. On d 16 of gestation, pregnant Sprague-Dawley rats were randomly assigned to either a retinoic acid group (intragastric ATRA at 10 mg/kg body weight) or a vehicle group. We punctured each amniotic sac, and fetuses in the opposite uterine horn served as controls. On d 21 of gestation, the fetuses were delivered by cesarean section. Rats subjected to oligohydramnios exhibited significantly lower lung weights and lung/body weight ratios, and ATRA had no effects on the body or lung weights of oligohydramnios-exposed rats. Lung PDGF-A and -B mRNA expression was significantly lower in oligohydramnios-exposed rats compared with control littermates of maternal vehicle-treated dams. Maternal retinoic acid treatment significantly increased PDGF-A and -B mRNA expression in control and oligohydramnios-exposed rats compared with all rats and oligohydramnios-exposed rats of maternal vehicle-treated dams, respectively. Rats exposed to oligohydramnios exhibited a significantly lower generation of alveolar saccules than did control rats in the maternal retinoic acid- and vehicle-treated groups. In this model, maternal retinoic acid treatment showed no positive effects on oligohydramnios-induced pulmonary hypoplasia in the pseudoglandular stage.

Topics: Amnion; Animals; Body Weight; Disease Models, Animal; Female; Fetal Organ Maturity; Gestational Age; Immunohistochemistry; Lung; Lung Diseases; Oligohydramnios; Organ Size; Platelet-Derived Growth Factor; Pregnancy; Proto-Oncogene Proteins c-sis; Pulmonary Alveoli; Rats; Rats, Sprague-Dawley; RNA, Messenger; Tretinoin; Up-Regulation

The treatment of acute promyelocytic leukemia with all-trans-retinoic acid (ATRA) sometimes results in a syndrome characterized by fever, respiratory distress, weight gain, pleural and pericardial effusion, and pulmonary infiltrates. We report the radiologic features of ATRA syndrome.. During the past 5 years, 69 patients with acute promyelocytic leukemia were treated with ATRA. Of this group, 15 patients developed ATRA syndrome. Serial chest radiographs of the 15 patients with ATRA syndrome were evaluated retrospectively for the presence of pleural effusion, pulmonary nodules, consolidation, ground-glass opacity, septal lines, increased pulmonary blood volume, peribronchial cuffing, and air bronchogram. Also, we measured the cardiothoracic ratio and the vascular pedicle width.. Chest radiographs showed increased cardiothoracic ratio in 13 of the 15 patients, increased vascular pedicle width in 13, increased pulmonary blood volume in 13, septal lines in nine, peribronchial cuffing in nine, ground-glass opacity in nine, consolidation in seven, and nodules in seven. Pleural effusion was noted in 11 of the 15 patients, and air bronchogram was noted in five of the 15 patients. Pulmonary hemorrhage developed in three patients who were being treated with ATRA; they showed bilateral, diffuse, poorly defined nodules and ground-glass opacity on radiography.. Most patients with ATRA syndrome have abnormal findings on chest radiographs, and the abnormalities are similar to those of pulmonary edema.

Topics: Adult; Antineoplastic Agents; Female; Fever; Humans; Lung Diseases; Male; Middle Aged; Pericardial Effusion; Pleural Effusion; Radiography; Syndrome; Tretinoin; Weight Gain

Impaired septal formation and decreased alveolarization are often caused by hyperoxic injury to the developing lung and are characteristic features of bronchopulmonary dysplasia. Dexamethasone, frequently administered to infants during oxygen exposure, also inhibits septal formation in the newborn lung. Vitamin A administration reduces the incidence of bronchopulmonary dysplasia in vitamin A-deficient premature infants, and retinoic acid improves alveolarization in newborn rats treated with dexamethasone, indicating that retinoic acid may be useful in preventing hyperoxia-induced impaired septation in bronchopulmonary dysplasia. To investigate whether treatment with retinoic acid during exposure to hyperoxia would improve septal formation, newborn rats exposed to > or =90% O(2) from d 3 of life to d 14 were treated with retinoic acid (d 3-13 of life) and/or dexamethasone (d 4-13 of life). In contrast with the effects of retinoic acid on dexamethasone-induced inhibition of alveolarization, we found that retinoic acid did not improve septal formation or decrease airspace size in animals exposed to hyperoxia alone or to hyperoxia plus dexamethasone. Retinoic acid did, however, increase collagen in airspace walls as demonstrated by staining and immunohistochemistry. There was no increase in procollagen mRNA by Northern hybridization analysis, indicating that retinoic acid-associated increases in lung collagen are likely due to posttranscriptional regulation. There was a trend toward increased survival in hyperoxia in animals treated with retinoic acid to the extent that combined therapy with retinoic acid and dexamethasone resulted in the greatest improvement in animal survival. These results suggest that although retinoic acid may be of benefit in hyperoxia-induced lung injury and may have important effects on lung matrix, it does not prevent impairment of septation or induce alveolar formation during exposure to hyperoxia.

Topics: Animals; Collagen; Dexamethasone; Gene Expression; Glucocorticoids; Hyperoxia; Immunohistochemistry; Lung; Lung Diseases; Lung Volume Measurements; Procollagen; Pulmonary Alveoli; Rats; Rats, Sprague-Dawley; RNA, Messenger; Tretinoin

All-trans-retinoic acid (ATRA) is considered the recommended induction treatment for acute promyelocytic leukemia. In the pre-ATRA era pulmonary bleeding was a common cause of death in these patients, mostly due to disseminated intravascular coagulation which was further exacerbated by the administration of chemotherapy. Although ATRA syndrome, the most serious adverse effect of ATRA treatment, involves the lungs, pulmonary hemorrhage has only rarely been reported as a manifestation of ATRA syndrome. Here we describe 2 patients who developed diffuse alveolar hemorrhage during treatment with ATRA. The possible mechanisms of pulmonary bleeding in these cases are discussed.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Blood Coagulation Tests; Cytarabine; Daunorubicin; Dyspnea; Fatal Outcome; Fever; Hemorrhage; Humans; Leukemia, Promyelocytic, Acute; Lung Diseases; Male; Middle Aged; Pulmonary Alveoli; Remission Induction; Syndrome; Tretinoin

Topics: Humans; Leukemia, Myeloid, Acute; Lung Diseases; Tretinoin

Topics: Epithelium; Eye Diseases; Humans; Lung Diseases; Mouth Diseases; Tracheal Diseases; Tretinoin; Vitamin A; Vitamin A Deficiency

Topics: Animals; Cricetinae; Emphysema; Hyaluronic Acid; Lung Diseases; Macrophage Activation; Macrophages, Alveolar; Trachea; Tretinoin

Topics: Humans; Leukemia, Promyelocytic, Acute; Lung Diseases; Male; Middle Aged; Syndrome; Tretinoin

All-trans retinoic acid has recently been shown to induce differentiation of acute promyelocytic leukemia cells in vitro and in vivo. Clinical trials of patients treated de novo, in first relapse, and with resistant disease have achieved a high rate of complete remission (CR). The overall toxicity is substantially less than standard induction chemotherapy, with the notable exception of deaths attributed to the development of pulmonary leukostasis coinciding with a rapid increase in the number of mature neutrophils. This report describes a patient who developed pulmonary leukostasis in the absence of significant leukocytosis. The patient survived pulmonary leukostasis, resumed therapy, and achieved a CR. The case demonstrates features of leukostasis which are peculiar to the 'retinoic acid syndrome'.

Topics: Humans; Leukemia, Promyelocytic, Acute; Leukocytes; Lung Diseases; Male; Middle Aged; Remission Induction; Tretinoin